Project Summary: A Novel Polymeric Valve for Transcatheter Aortic Valve Replacement Minimally invasive transcatheter aortic valve replacement (TAVR) has emerged as an effective therapy for the unmet clinical need of inoperable patients with severe aortic stenosis (AS). Recent longitudinal follow-up studies of TAVR patients however indicate that this procedure and associated technology may result in serious adverse events. Current technology is based on tissue valves adapted to, but not specifically designed for TAVR. Those may sustain damage during crimping as well as deployment, are susceptible to ?bone-like? calcific deposition, and suffer from limited durability. In a collaboration between Stony Brook University and PolyNova Cardiovascular, Inc., we have developed a novel valve that is specifically designed to tackle the numerous challenges that a TAVR valve will meet during its life cycle, from crimping to deployment and long term performance in situ. It incorporates (i) novel polymer technology, xSIBS, which combines superior bio-stability together with excellent mechanical properties, and (ii) a novel design optimization methodology of the leaflets profile for enhanced hemodynamics, durability, and thromboresistance performance. Our broad objective is to develop a viable and durable TAVR valve that will propose a real alternative to existing bioprosthetic aortic valves, and allow a long-term solution adequate for broader segment of the population. Following a successful Phase I STTR project, in this Phase II project we aim to expand the R&D activities of our polymeric valve toward First-In-Man, and implement a robust regulatory and quality management system plans. The proposed project includes 4 Aims: Aim 1 expand our set of advanced computational flow simulations, development of a 2nd generation valve, development of a dedicated delivery catheter system, and expanding our valve product to a complete set of valve sizes. Aim 2 tests the valve performance according to the ISO 5840-3 (transcatheter heart valves), ISO 25539-1 (cardiovascular implants), and ISO10993-1 (biocompatibility). We will also modify our valve manufacturing capabilities to be compliant with the FDA quality management system. Aim 3 tests the valves in vivo in sheep model. The valves are tested for efficacy and safety in acute tests as well as chronic 10 and 20 wks. Aim 4 is dedicated for integrating regulatory and business plans for PolyNova and for the valve technology. Integral to this STTR Phase II project is a detailed commercialization and regulatory plan, based on which, and under the support of this Phase II program, we will convert PolyNova from a pure R&D shop to firm establishment as a qualified medical device manufacturer? i.e. institution of a fully cGMP, FDA compliant Quality Management System including a robust Design Control process. Successful accomplishment of the above aims will lead to a breakthrough in the treatment of aortic valve diseases, providing an affordable, long-term, minimally invasive solution, enhancing the life of a much broader patient population.